Varicella zoster virus (VZV) is the most common virological cause of disease in the elderly. Primary infection causes varicella, after which virus becomes latent in ganglia along the entire neuraxis. By 2050, >83 million Americans will be >65 years old with 95% harboring latent VZV. As the immune system ages, VZV will reactivate in >50% of Americans by 85 years of age to produce zoster, which can be complicated by postherpetic neuralgia. During reactivation, VZV can also cause giant cell arteritis (GCA), which is the most common systemic vasculitis in the elderly characterized by severe headache and scalp tenderness, as well as a history of jaw claudication, polymyalgia rheumatica, fever, night sweats, weight loss, fatigue, and elevated serum inflammatory markers. GCA is a medical emergency that leads to vision loss; thus, patients are treated with corticosteroids, with 50% relapsing or progressing to stroke and vision loss despite therapy. By 2050, in the US, the estimated cost from visual impairment due GCA will exceed $76 billion. TA biopsy from GCA patients typically reveals transmural inflammation, medial damage and multinucleated giant/epithelioid cells (GCA-positive TAs) but may be pathologically negative (GCA-negative). Recently, we showed that 70% GCA- positive TAs and 58% GCA-negative TAs contain VZV antigen, as well as VZV DNA and herpesvirus particles in a subset, whereas only 18% normal TAs contained VZV antigen. The pathologic finding in GCA-positive and -negative TAs is persistent inflammation leading to vascular wall damage that we suspect is triggered by VZV infection. Taken together, we hypothesize that VZV elicits persistent vascular inflammation in TAs of patients with giant cell arteritis through production of a proinflammatory environment and recruitment of VZV-specific T cells. We will test this hypothesis by analyzing the proinflammatory environment and identifying biomarkers and pathways supportive of VZV infection in FFPE GCA-positive, GCA-negative and normal TAs with and without VZV antigen using TempO-Seq and pathway analysis programs (Aim 1) and determining if VZV- specific CD4 T cells are locally enriched in fresh TA biopsies of GCA (Aim 2). Elucidating the role of VZV in GCA will provide information on promising pathways to target in order to mitigate GCA and on biomarkers for disease susceptibility that may be extended to other VZV vasculopathies, ultimately guiding clinical decision- making and therapies, as well as improving quality of life and reducing health care costs. Successful completion of these Aims is supported by multidisciplinary collaborations by experts in neurology, ophthalmology immunology bioinformatics/statistics, the availability of archived FFPE TAs and fresh biopsy tissue and excellent environment of neurovirologists at the University of Colorado Department of Neurology. Elucidating the role of VZV in GCA will provide information on promising pathways to target in order to mitigate GCA and on biomarkers for disease susceptibility that may be extended to other VZV vasculopathies, ultimately guiding clinical decision-making and therapies, as well as improving quality of life and reducing health care costs.